Exogenous d‐β‐hydroxybutyrate lowers blood glucose in part by decreasing the availability of L‐alanine for gluconeogenesis

BACKGROUND: Interventions that induce ketosis simultaneously lower blood glucose and the explanation for this phenomenon is unknown. Additionally, the glucose‐lowering effect of acute ketosis is greater in people with type 2 diabetes (T2D). On the contrary, L‐alanine is a gluconeogenic substrate secreted by skeletal muscle at higher levels in people with T2D and infusing of ketones lower circulating L‐alanine blood levels. In this study, we sought to determine whether supplementation with L‐alanine would attenuate the glucose‐lowering effect of exogenous ketosis using a ketone ester (KE). METHODS: This crossover study involved 10 healthy human volunteers who fasted for 24 h prior to the ingestion of 25 g of d‐β‐hydroxybutyrate (βHB) in the form of a KE drink (ΔG(®)) on two separate visits. During one of the visits, participants additionally ingested 2 g of L‐alanine to see whether L‐alanine supplementation would attenuate the glucose‐lowering effect of the KE drink. Blood L‐alanine, L‐glutamine, glucose, βHB, free fatty acids (FFA), lactate and C‐peptide were measured for 120 min after ingestion of the KE, with or without L‐alanine. FINDINGS: The KE drinks elevated blood βHB concentrations from negligible levels to 4.52 ± 1.23 mmol/L, lowered glucose from 4.97 ± SD 0.39 to 3.77 ± SD 0.40 mmol/L, and lowered and L‐alanine from 0.56 ± SD 0.88 to 0.41 ± SD 0.91 mmol/L. L‐alanine in the KE drink elevated blood L‐Alanine by 0.68 ± SD 0.15 mmol/L, but had no significant effect on blood βHB, L‐glutamine, FFA, lactate, nor C‐peptide concentrations. By contrast, L‐alanine supplementation significantly attenuated the ketosis‐induced drop in glucose from 28% ± SD 8% to 16% ± SD 7% (p < .01). CONCLUSIONS: The glucose‐lowering effect of acutely elevated βHB is partially due to βHB decreasing L‐alanine availability as a substrate for gluconeogenesis.